3-cyclopentyl and cyclopentenyl ethers of estrone and derivatives thereof



United States Patent 3,159,543 S-CYCLOPENTYL AND CYLQPENTENYL ETPERS OFESTRUNE AND DERT VATHVES TEEREOF Alberto Ercoli, Milan, Italy, assignor to-Francesco Visrnara S.p.A., Casatenovo, Como, Italy, a corporation of Htaly N0 Drawing. Continuation of application Ser. No. 111,178, May 19, 1961. This application July 30, 1963, Ser. No. 2%,541 Claims priority, application Italy, Apr. 7, 1961, 6,44W 61 16 Claims. (Cl. 167--74) This invention relates to new derivatives of estrogen hormones and is more particularly concerned with novel five-membered cyclicethers of derivatives of 1,3,5-estratriene-3 -01 having an oxygen function at C Exemplary of the new Compounds of this invention are the cyclopentyl ethers of 3-hydroXy-17-keto estratriene (estrone), of 3,16u,17/3-trihydroxy estratriene (estriol), of 3,l6oc,17 octrihydroxy-estratriene (epiestriol), of 3,17fi-dihydroxyestratriene (estradiol), of the 17a-lower alkyl and ethynyl derivatives of estradiol and of the l7fl-acyl esters of estradiol and its 17oc-1OW61' alkyl and ethynyl derivatives.

It is an object of the present invention to provide new chemical compounds having a significant estrogenic activity. Another object of the invention is to provide pharmaceutical compositions containing the new compounds and a further object of the invention is to provide a method of carrying out estrogenic therapy in women employing these compositions.

The new compounds of this invention can be represented by one of the structural formulas:

where R represents a ketonic oxygen 0), a fi-hydroxy group, a fi-acyloxy group derived from a hydrocarbon monocarborryltic acid, particularly an alkanoic acid containing 1 to 4 carbon atoms, a [j -hydroXy'u-ethynyl group 1 3,159,543 Patented Dec. 1, 1964 where R represents a ketonic oxygen (=0) or an on or 'B-hydroxy group and R has the same meaning as above. It is preferred that R represent a cyclopentyl radical of the structure,

CIElIy OH CH- I Biz-CH; but it is to be understood that compounds in which there is unsaturation in the five carbon ring are included in the invention.

The compounds of this invention are physiologically active agents possessing, when administered orally, an exceptional estrogenic activity by far superior to that of the corresponding free 3-hydroxy steroids.

cording to the technique of Rubin et a1. (Endocrinology I49, 429, 1951), employing immature female mice, 20-

1 orally once daily for three consecutive days, with autopsy on the morning of the fourth day.

The initial and final body weights, and the uterus weight, have served as end-points.

a B-acyloxy a-ethynyl grouping in which the acyloxy bon atoms, or

In Table I are summarized the results of these investigations, giving the uterotrophic activity of representative cyclopentyl ethers of this invention, and some of the corresponding lower alkyl and aralkyl others, taking as 1 the potency of the parent steroid.

TABLE I Relative uterotrophic Compound: potencies Estrone p 1 3-propyl ether 0.6 -butyl ether 1.5 -benzy1 ether 0.5 -cyclopentyl ether 15 Estriol 1 3-buty1 ether 1.2 -cyclopentyl ether 25 Epi-estriol 1 3-cyclopentyl ether 20 Estradiol l 3-butyl ether 1 -benzyl ether 0.3 -cyclopentyl ether 10' 17cz-methyl' estradiol 1 3-cyclopentyl ether 15 17a-ethynyl estradiol 1 3-methyl ether 0.3 -cyclopentyl ether 3 The new cyclopentyl ethers ofthis invention show an The cyclopentyl ethers of estriol and epi-estriol are also effective when given by parenteral route and they show by this route an effectiveness about twenty times greater than the corresponding parent hormones.

The new cyclopentyl ether derivatives of this invention, which possess a marked intrinsic estrogenic activity, are of practical value, especially by oral administration, because they permit an oral treatment with low dosages.

Such compounds can be given orally in association with a suitable pharmaceutical carrier which is not incompatible with the active substance. The carrier can be solid or liquid and can be chosen among those usually employed in pharmaceutical techniques for manufacturing preparations suitable for oral ingestion. According to the nature of the carrier, the compositions will be in solid or liquid form. In the first case they may take the form of pills, tablets, sweets, capsules, etc., and in the second case, they may take the form of syrup or suspensions. If desired, the liquid preparations may be contained in capsules of gelatin or other material soluble or disintegrateable in the alimentary tract. As acceptable carriers, there can be used oils, which are liquid, or fats or butteers, which are solid or semi-solid at ordinary atmospheric temperatures.

A suitable way to administer the pentyl ethers of estrogen hormones is to give them orally dissolved in a fluid vehicle, such as a vegetable oil or an orally-acceptable alcohol or glycol, sufficient of the vehicle being present to dissolve and carry the active substances.

In the compositions of this invention, the new compounds are present in an amount sufiicient to produce therapeutic effects. In general, the amount is from about 0.001 mg. to about 10 mg, preferably from about 0.01 mg. to about 5 mg. per dosage unit.

The method of this invention comprises orally administering the new compounds to humans, in an amount sufiicient to produce therapeutic efiects, in admixture with a non-toxic pharmaceutical carrier as exemplified above. The daily dosage of the B-ethers will be in an amount of from about 0.001 mg. to about 30 mg. and preferably from about 0.01 mg. to about mg. The administration is by the oral route, in equal doses, one to three times daily.

The new compounds of this invention may be also administered orally in association with other therapeutically useful substances, such as, for example, enol ethers of androgenic and/or progestational hormones. The enol ethers of androgenic hormones include preferably hexyl and cyclopentyl enol ether of 17oc-methyltestosterone and the enol ethers of progestational hormones may be selected from the cyclopentyl enol ethers of progesterone, 17x-acetoxy progesterone and l7a-ethynyl l9-nortestosterone acetate.

Preparation and use of the composition of this invention comprising, in combination with the cyclopentyl ethers of estrogen hormones, one or more of the enol ethers said above, are illustrated in the examples.

The new compounds of this invention can be obtained by methods already known for the preparation of other ethers. The cyclopentyl ether of estrone can be easily prepared by reacting 3-hydroxy-l7-keto-estratriene or its sodium salt with the cyclopentyl halide, for instance bromide or chloride, in the presence of a suitable condensing agent and thereafter recovering the desired ether from the mixture of reaction products. As condensing agent, an alkaline hydroxide or carbonate or alcoholate can be employed. The same procedure can be followed for the preparation of cyclopentyl ethers of estriol and epiestriol.

The preparation of the cyclopentyl monoethers of 3,17- dihydroxy-estratriene can be carried out either directly by submitting the diol to partial etherification, or indirectly by first preparing the cyclopentyl monoether of the corresponding 3-hydroxy-17-keto-estratriene and then transforming the 17-keto group into a hydroxy group by normal reduction methods. The same procedure Example 1 A mixture of 1 g. of estrone and 1 g. of cyclopentyl bromide is added slowly to a solution of sodium ethylate, obtained from 0.1 g. of sodium and 8 cc. of absolute ethanol. The reaction mixture is heated to reflux for 4 hours, then ethyl alcohol is eliminated by distillation and the residue treated with a little water. A precipitate is obtained consisting of cyclopentyl ether of estrone which, after recrystallization from a mixture of methylene chloride-methanol, melts at 149-150 C.; [a] =l-136 (0.5% in dioxane).

Example 2 0.2 g. of potassium hydroxide are dissolved in 10 cc. of absolute ethanol and to the solution is added slowly a mixture of 1.2 g. of estradiol and 1 g. of cyclopentyl chloride. After heating to reflux for three hours, the solvent is evaporated, and the residue treated with water, thus obtaining 1.5 g. of a product which, filtered, washed with a little water and dried, melts as 109 C. After recrystallization from methanol, 1.1 g. of estradiol 3- cyclopentyl ether is obtained at M.P. 1161l8.5 C.; [a] =-l-63.5i1 (0.5% in dioxane).

0.5 g. of this ether dissolved in 4 cc. of anhydrous pyridine are treated with 2 cc. of propionic anhydride. The mixture is allowed to stand for approximately 15 hours, then poured into water, causing a solid to precipitate. The product is collected, washed and dried to give 0.45 g. of estradiol 17-propionate i i-cyclopentyl ether which, after recrystallization from methanol, melts at l0ll0-2 C.; [a] =+41 (0.5% in dioxane).

Example 3 To a suspension of 2 g. of estrone cyclopentyl ether in 50 cc. of ethanol are added 0.2 g. of sodium borohydride in 3 cc. of water soultion. This mixture is stirred for about 6 hours at room temperature, then treated with 10 cc. of acetic acid and diluted with water up to complete precipitation. The product filtered and dried, consists of 3-cyclopentyl ether of estradiol melting at 110 C.

Example 4 Example 5 A solution of potassium ter-amylate obtained from 2 g. of potassium and 40 cc. of tertiary amyl alcohol, is saturated with acetylene,'2 g. of estrone cyclopentyl ether in 50 cc. of anhydrous toluene solution are added and addition of acetylene is continued for ten hours at a temperature of about 20 C.

The reaction mixture is then treated with cc. of

an aqueous solution of ammonium chloride, the organic layer separted, washed with water, dried over anyhdrous sodium carbonate and evaporated to dryness to give 1,7 g. of a crude product, which recrystallized from methanol, melts at l06-l07 C. The melting point is undepressed on admixture with a specimen of 3-cyclopentyl ether of 17ot-ethyny1 estradiol obtained as in Example 4.

This compound (1 g.) is treated with 4 cc. of propionic anhydride in pyridine solution as in Example 2 to give ether.

Example 6 A mixture of 1.5 g. of estriol and 1.5 g. of cyclopentyl bromide in cc. of sodium ethylate solution, containing 0.2 g. of sodium, is refluxed for three hours, then ethyl alcohol is eliminated by distillation and the residue de composed with a little water to give 1.7 g. of estriol 3- cyolopentyl ether, M.P. 16l162 C.; [cc] =+46 (dioxane).

Example 7 To 1.1 g. of estrone there are added 35 cc. of absolute methanol, 1.9 g. of 3-cyclopentyl chloride and 1.6 g. of potassium carbonate. The mixture is refluxed for two hours under nitrogen atmosphere and absolutely anhydrous conditions, then cooled and filtered from the potassium salt which separates.

The solvent is eliminated and the residue recrystallized from anyhydrous methanol to give cyclopentenyl ether of estrone.

Example 8 By treating 1 g. of 17-epiestriol with 1 cc. of cyclopentyl bromide in a sodium ethylate solution as in Example 1, 17-epiest-rio1 3-cyolopentylether is obtained melting, after recrystallization from hexane, at 1l41l5 C.; [a] :+4O (dioxane).

Example 9 A mixture of 1 g. of 17a-methylestradiol and 1 cc. of

cyclopentyl bromide is added to a solution of sodium 1 ethylate obtained from 0.1 g. of sodium and 15 cc. of absolute ethanol. The reaction mixture is heated to reflux for 4 hours, then partially concentrated under vacuum after addition of a little water.

A precipitate is obtained consisting of 3-cyelopentyl ether of 17a-methylestradiolwhich, after recrystallization from hexane, melts at 107108 C.; [a] =+45 (dioxane).

1 Example 10 A solution of 1 g. of estrone 3-cyclope-ntyl ether in 10 cc. of anhydrous tetrahydrofuran is added to an ethereal solution of methylmagnesium bromide obtained from 2 g. of magnesium and g. of methyl bromide. The reaction mixture is heated to reflux for 2 hours and then allowed to stand overnight at room temperature. The mixture is thentreated with an aqueous solution of ammonium chloride. The organic layers are separated, washed with water, dried over anhydrous sodium carbonate and evaporated to dryness togive flu-methylestradiol 3-cyclopentyl ether.

The compound (0.5 g.) is treated with propionicanhydride and pyridine and converted into 17B-propionate of 17a-methyl estradiol 3-cyclopentyl ether.

Example 11 1 g. of cyclopentyl ether of estradiol dissolved in 5 cc. of anhydrous pyridine,,is refluxed for about one hour with 2 g. of acetic anhydride. After cooling, the mixture is diluted with water causing the precipitation of a product which is collected by filtration, dried and recrystallized from methanol, thus obtaining the 3-cyclo- ,pentyl ether of estradiol 17 3-acetate.

10 l7-B-propionate of 17a-ethynyl est-radiol 3-cyclopentyl with good results.

6. Similarly, estradiol cyclopentyl ether is esterified with isobutyric anhydride and pyridine to give estradiol 17,8- isobutyrate 3-cyclopentyl ether.

Example 12 Example 7 yields cyclopenrtenyl ether of 17a-ethynyl- V estradiol.

Example 13 1 g. of cyclopentyl ether of estrone is dissolved in 20 cc. of tetrahydrofuran. To the resulting solution there is added 0.1 g. of sodium borohydride in 5 cc. of water solution and the mixture is stirred for some minutes, at room temperature (about 20 C.), then heated at reflux for about one hour.

After cooling, a little water is poured into the reaction flask up to complete precipitation of the cyclopentyl ether.

500 mg. of this product are dissolved in 3 cc. of 99% formic acid and to the resulting solution 25 mg. of p-toluenesulfonic acid are added. The mixture is stirred vigorously for a few minutes, then allowed to stand for about fifteen hours at a temperature of about 15 C. After addition of water, a precipitate is obtained of estradiol -17fi-formate-3-cyclopentyl ether. Yield 65 of the theoretical amount.

Example 14 l7a-ethylestradiol (0.5 g.) is treated with 0.6 cc. of cyclopentyl bromide in 8 cc. of sodium ethylate solution, as described in Example 9, to give 3-cyclopentyl ether of 17a-ethylestradiol.

This material (0.02 mg.) is mixed with 10 mg. of'

lactose and filled into gelatine capsules which are administered orally one or two times daily. The capsules are used clinically for relief of the menopausal symptoms and in secondary amenorrhea.

Example 15 Tablets for oral use, each containing 0.1 mg. of estradiol 3-cyclopentyl ether, are prepared from the following com ponents:

Cyclopentyl ether of estradiol mg 100 Placebo granules g 40 Talc g 5 Calcium stearate g 5 The placebo granules are made of 60% lactose and 40% of rich starch. The finely powdered cyclopentyl ether of estradiol is added and the adjuvants talc and calcium stearate are added. Tabieting is done on a rotary machine.

Example 16 Example 1.7

Gelatin capsules, each containing 0.1 mg. of cyclopentyl ether of estriol in 0.2 cc. of sesame oil solution, are prepared in the usual manner and used clinically in the treatment of senile vaginitis, kraurosis vulvae and leukoplakia Example 18 3-cyclopentyl ether of estrone (210 mg.) are dissolved in 210 cc. of sesame oil and the solution is poured in 3 cc.

ampoules, so that each ampoule contains 1 mg./ cc. of the active substance. Such an oil composition, which is of proper dosage, is suitable for oral ingestion when administered dropwise.

Example 19 In the same manner as in the preceding examples, liquid compositions for oral use, containing 3-cyclopentyl ether of e iestriol, estradiol, 17a-methyl and ethyl estradiol are prepared by using sesame oil, olive oil or other vegetable oil, singly or in admixture as liquid carriers.

Example 20 Gelatin capsules, each containing 5 mg. of 3-cyclopentyl enolether of 17a-rnethyltestosterone and 0.2 mg. of cyclopentyl ether of estradiol in 0.5 cc. of sesame oil, are prepared by dissolving the active ingredients in a calculated amount of the oil and then encapsulating the solution in the usual manner.

The capsules are used clinically for inhibition and suppression of lactation, at a dose of two to three capsules daily.

In the same manner as above, hard gelatin capsules are prepared each containing 6 mg. of 3-hexyl enolether of 17a-methyltestosterone and 0.2 mg. of 3-cyclopentyl ether of estradiol.

Example 21 Example 22 An oily composition suitable for oral administration, comprising one androgenic, one estrogenic and one progestinic substance, is prepared by dissolving in a mixture of sesame oil and olive oil 3-n-hexyl enolether of 17amethyltestosterone (l5 mg./cc.), 3-cyclopentyl enolether of progesterone ing/cc.) and 3-cyclopentyl ether of 17a-ethynyl estradiol (0.05 mg./cc.).

The solution is then encapsulated in the usual manner and the capsules used clinically for the treatment of profuse vaginal bleeding during or after the menopause, at a dose of two capsules daily.

This application is a continuation of my US. application Serial No. 111,178, filed May 19, 1961, now abandoned, which is, in turn, a continuation-in-part to my US. application Serial No. 26,714, filed on May 4, 1960, now abandoned.

I claim:

l. A steroid compound selected from the group consisting of a compound having the formula:

where R is selected from the group consisting of a keto group, a fi-hydroxy group, a fl-acyloxy group derived from a lower alkanoic acid, a fi-hydroxy u-alkyl grouping in which the alkyl group contains from one to three carbon atoms, a ,B-acyloxy e-alkyl grouping in which the acyloxy group is derived from a lower alkanoic acid and the alkyl group contains from one to three carbon atoms, a fi-hydroxy a -ethynyl grouping, a fiacyloxy a-ethynyl grouping in which the acyloxy group is derived from a lower alkanoic acid and R is a member selected from the group consisting of cyclopentyl and cyclopentenyl radicals, and a compound having the formula where R has the same meaning as above, and R is selected from the group consisting of aand B-hydroxy groups.

2. 3-cyclopentyl ether of estrone. 3-cyclopentyl ether of estriol. 3-cycl0pentyl ether of epi-estriol. 3-cyclopentyl ether of estradiol. 3-cyclopentyl ether of l7 x-methyl estradiol. 3-cyclopentyl ether of 17a-ethynyl estradiol. A pharmaceutical composition in dosage unit form for oral administration comprising in admixture with a pharmaceutically acceptable carrier, from 0.001 mg. to 10 mg. of a steroid compound selected from the group consisting of a compound having the formula:

where R is selected from the group consisting of a keto group, a ,B-hydroxy group, a fi-acyloxy group derived from a lower alkanoic acid, a fl-hydroxy a-alkyl grouping in which the alkyl group contains from one to three carbon atoms, a fl-acyloxy u-alkyl grouping in which the acyloxy group is derived from a lower alkanoic acid and the alkyl group contains from one to three carbon atoms, a fi-hydroxy a-ethynyl grouping, a fi-acyloxy u-ethynyl grouping in which the acyloxy group is derived from a lower alkanoic acid and R is a member selected from the group consisting of cyclopentyl and cyclopentenyl radicals, and a compound having the formula where R has the same meaning as above, and R is selected from the group consisting of ocand ,B-hydroxy groups.

9. A composition as claimed in claim 8 containing from 0.01 mg. to 5 mg. of said steroid compound.

10. A composition as claimed in claim 8 in which said carrier includes an orally acceptable vegetable oil.

compound is the 3-cyclopentyl enol ether of estradiol,

and said androgenic hormone is the 3-cyclopcntyl enol ether of 17a-methyltcstosterone.

13. A composition as claimed in claim 8 which also includes a S-cyclopentyl enol ether of a progestational patient from 0.001 mg. to 30 mg. of a steroid compound selected from the group consisting of a compound having the formula where R is selected from the group consisting of a keto group, a B-hydroxy group, a B-acyloxy group derived from a lower alkanoic acid, a fl-hydroxy walkyl grouping in which the mkyl group contains from one to three a carbon atoms, a B-acyloxy a-alkyl grouping in which the acyloxy group is derived from a lower alkanoic acid and the alkyl group contains from one to three carbon atoms, a fl-hydroxy u-ethynyl grouping, a fi-acyloxy a-ethynyl grouping in which the acyloxy group is derived from a lower alkanoic acid and R is a member selected from the group consisting of cyclopentyl and cyclopentenyl radicals, and a compound having the formula o5 3on3 where R has the same meaning as above, and R is selected from the group consisting of 0cand fi-hydroxy groups.

16. A processas claimed in claim 15 in which there is daily administered from 0.01 mg. to 10 mg. of said steroid compound.

References Cited in the file of this patent UNITED STATES PATENTS 2,949,476 Tyner Aug. 16, 1960 

15. A PROCESS OF CARRYING OUT ESTROGENIC THERAPY FOR A HUMAN PATIENT COMPRISING ADMINISTERING DAILY TO SAID PATIENT FROM 0.001 MG. TO 30 MG. OF A STEROID COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING THE FORMULA 